Rearrangement of Benzylic Trichloroacetimidates to Benzylic Trichloroacetamides

Article abstract of DOI:10.1021/acs.joc.7b00245

The rearrangement of allylic trichloroacetimidates is a well-known transformation, but the corresponding rearrangement of benzylic trichloroacetimidates has not been explored as a method for the synthesis of benzylic amines. Conditions that provide the tr

Full text of DOI:10.1021/acs.joc.7b00245

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Note
Rearrangement of Benzylic Trichloroacetimidates
to Benzylic Trichloroacetamides
Arijit A Adhikari, Tamie Suzuki, Reesheda J Gilbert, Matthew R Linaburg, and John Daniel Chisholm
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Mar 2017
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Rearrangement of Benzylic Trichloroacetimidates to
Benzylic Trichloroacetamides
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Arijit A. Adhikari, Tamie Suzuki, Reesheda J. Gilbert, Matthew R. Linaburg and John D.
Chisholm*
Department of Chemistry, 1ꢀ014 Center for Science and Technology, Syracuse University,
Syracuse, NY 13244
jdchisho@syr.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal you are submitting your paper to)
1 mol %
BF3•OEt2
MeNO2
0°C, 10 min
R
O
R
NH
CCl3
N
CCl3
O
or
MeNO2
X
X
H
reflux, 22 h
Abstract
The rearrangement of allylic trichloroacetimidates is a wellꢀknown transformation, but the
corresponding rearrangement of benzylic trichloroacetimidates has not been explored as a
method for the synthesis of benzylic amines. Conditions that provide the trichloroacetamide
product from a benzylic trichloroacetimidate in high yield have been developed. Methods were
also investigated to transform the trichloroacetamide product directly into the corresponding
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amine, carbamate and urea. A cationic mechanism for the rearrangement is implicated by the
available data.
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Benzylic amines are commonly encountered in the structures of pharmaceuticals,
biologically active natural products, insecticides, and food additives.1 Due to their prominent
position in the pantheon of functional groups, a variety of techniques have been explored for the
preparation of benzylic amines. Common precursors include benzylic alcohols, which are
commonly converted to the corresponding amine using the Gabriel amine synthesis,2 the
Mitsunobu reaction3 and "borrowing hydrogen" methodology.4 While these methods are
effective, they all require either transition metal catalysts or generate significant waste streams.
The rearrangement of allylic trichloroacetimidates to trichloroacetamides is often employed
in the synthesis of allylic amines.5 The related benzylic transformation has received little
attention, but potentially could provide rapid entry to benzylic trichloroacetamides that may be
elaborated into benzylic amines or their protected variants. Cramer first reported that some alkyl
and benzylic trichloroacetimidates rearranged to the corresponding trichloroacetamides when
exposed to a Lewis acid.6 Later Schmidt and coꢀworkers observed that some glycosidic
trichloroacetimidates provided small amounts of the corresponding acetamide product.7 A
number of other examples have been reported with glycosidic trichloroacetimidates,8 and these
results have recently been reviewed.9 More recently Motawia and coꢀworkers described
conditions for promoting the rearrangement of glycosyl trichloroacetimidates to glycosyl
trichloroacetamides utilizing catalytic TMSOTf.10 Nguyen and coꢀworkers have also developed a
transition metalꢀcatalyzed rearrangement of glycosyl trichloroacetimidates to the corresponding
acetamides, which are utilized in the synthesis of glycosyl ureas.11 Some specific
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trichloroacetimidate systems (such as αꢀmethyleneꢀβꢀtrichloroacetimidate alkanoates,12 αꢀdiazoꢀ
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6
7
8
βꢀtrichloroacetimidate carbonyl compounds13 and "doubly activated" imidates, being both
benzylic and propargylic14) rapidly rearrange to the trichloroacetamide, which may preclude
isolation of the imidate.
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During some recent studies on alkylations utilizing trichloroacetimidates as electrophiles
without the addition of an exogenous catalyst,15 it was observed that the rearrangement of
trichloroacetimidate 1 to acetamide 2 was rapid and could be effected simply by heating (Scheme
1).15a,15c In order to evaluate the possibility of utilizing this transformation in the synthesis of
protected benzylic amines, a study was undertaken to determine if the yield and rate of the
reaction could be improved.
Scheme 1. Rearrangement of DPM Imidate 1
NH
O
O
CCl3
1
HN
Ph
CCl3
46%
toluene
reflux, 22 h
2
Ph
Ph
Ph
Initially some concern was expressed that the rearrangement of imidate 1 may be a special
case, as imidate 1 is a precursor to the especially stable diphenyl methyl cation. Should cation
formation be critical, this would limit the scope of the transformation. Furthermore, imidate 1
cannot undergo elimination, which has been observed to be a competing side reaction in other
substrates.14 Therefore a less biased system, the phenethyl trichloroacetimidate 3, was utilized
for optimization (Table 1). Initially thermal conditions were explored by heating imidate 3
without an added catalyst. Nonpolar aromatic solvents like toluene and mꢀxylene gave mainly
decomposition under these thermal conditions (entries 1 and 2). Alternatively, only starting
material was observed with 2ꢀmethylꢀ2ꢀbutanol (entry 3). Some conversion was achieved with
1,4ꢀdioxane and propionitrile (entries 4 and 5), but nitromethane gave significantly improved
results, providing an 80% isolated yield. While trace amounts (3ꢀ4%) of elimination could be
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observed in the crude H NMR when 1,4ꢀdioxane and propionitrile were used, no elimination
byproduct was observed with nitromethane. Previously nitromethane was shown to enhance the
reactivity of tertꢀbutyl trichloroacetimidate towards substitution in the alkylation of anilines.16
This was attributed to the ability of nitromethane to facilitate cation formation without
elimination, which may also explain the excellent yield in the thermal rearrangement. One
limitation of the thermal reaction was the long reaction time. To increase the rate of the
transformation, Brønsted and Lewis acid catalysts were evaluated (Table 1, entries 7ꢀ16). Most
Brønsted acid catalysts resulted in slow reactions at room temperature (entries 7 and 8), but
triflic acid provided complete rearrangement in only 10 min (entry 9). While promising, the use
of strong Brønsted acids like triflic acid may limit functional group compatibility, and therefore a
number of Lewis acids were evaluated. Mild Lewis acids like CuBr2 and CuCl2 (entries 10 and
11) led to slow reactions, while stronger Lewis acids like ZnCl2, FeCl3 and BF3•OEt2 (entries 12ꢀ
14) gave rapid rearrangement and excellent conversion. In the case of BF3•OEt2, the catalyst
loading could be lowered to 1 mol % without a significant drop in reaction rate, providing 93%
isolated yield in just 10 min. Two sets of conditions from Table 1 seemed worth exploring, the
catalyst free thermal transformation (entry 6) and the BF3•OEt2 catalyzed conditions (entry 15),
as some substrates that may not be stable to one set of conditions may rearrange under the
alternate conditions, and so both conditions were evaluated further.
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Table 1. Optimization of the Rearrangement of Imidate 3 to Acetamide 4.
CH3 NH
CH3
O
conditions
5
Ph
O
CCl3
Ph
N
CCl3
3
4
H
6
7
8
9
NMR
entry
reaction conditions
toluene, reflux, 22 h
mꢀxylene, reflux, 16 h
yielda yieldb
1
2
3
4
5
6
7
4
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
0c
10
11
12
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15
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21
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2ꢀMeꢀ2ꢀbutanol,reflux, 22 h
1,4ꢀdioxane, reflux, 16 h
EtCN, reflux, 24 h
MeNO2, reflux, 22 h
10 mol % (PhO)2PO2H
MeNO2, rt, 27 h
0d
18e
4e
80
10
80
ꢀ
8
9
10
11
12
10 mol % CSA, MeNO2, rt, 27 h
20
ꢀ
80
ꢀ
ꢀ
ꢀ
10 mol % TfOH, MeNO2, rt, 10 min 85
10 mol % CuBr2, MeNO2, rt, 20 h
10 mol % CuCl2, MeNO2, rt, 20 h
10 mol % ZnCl2, MeNO2, rt, 1 h
55
74
90
13 10 mol % FeCl3, MeNO2, rt, 10 min 93
88
90
14
15
16
10 mol % BF3•OEt2
MeNO2, rt, 10 min
1 mol % BF3•OEt2
MeNO2, 0 °C, 10 min
1 mol % FeCl3
91
94
25
94
ꢀ
MeNO2, 0 °Cꢀrt, 40 h
aDetermined by 1H NMR using mesitylene as an internal standard. bIsolated yield (%). cStarting material
decomposed. dStarting material was recovered. eTrace amounts of styrene were detected in the 1H NMR
A number of trichloroacetimidates were then subjected to both sets of rearrangement
conditions (Table 2). Incorporation of electronꢀdonating groups on the aromatic ring generally
led to very good yields of the acetamide product under both thermal and Lewis acid catalyzed
conditions (entries 2ꢀ4). Weak deactivating groups like chloride still gave an acceptable yield
(entry 5), although the addition of a strongly deactivating nitro group was detrimental (entry 6).
Indeed, trichloroacetimidate 15 was inert under the thermal conditions, and only gave
rearrangement product in 32% yield under more vigorous Lewis acid catalyzed conditions (10
mol % BF3•OEt2, nitromethane, reflux, 24 h). Placing a halogen or methyl group at the ortho
position of the aromatic ring lowered the isolated yields of the corresponding trichloroacetamide
(entries 7ꢀ9), which was attributed to unfavorable steric factors. Replacing the benzene ring with
an indole, as in the case of trichloroacetimidate 23, (entry 10) provided the rearranged product
with good yield (72%) under Lewis acid catalyzed conditions, however under thermal conditions
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the imidate rapidly decomposed. This demonstrates the flexibility of having both thermal and
Lewis acid catalyzed protocols available, as some substrates may not be compatible with both
sets of conditions. Primary benzylic trichloroacetimidates (entry 11 and 12) provided lower
yields than the secondary substrates. Strong electron withdrawing substituents on the adjacent
aromatic ring were again detrimental, as shown with 4ꢀnitrobenzyl imidate 29.
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Table 2. Rearrangement of Primary and Secondary Trichloroacetimidates
MeNO2
reflux, 24 h or
R
NH
CCl3
R
O
Ar
O
Ar
N
CCl3
1 mol % BF3•OEt2
MeNO2, 0°C, 10 min
5
6
H
entry
1
imidate
acetamide
yielda yieldb
CH3 NH
CH3
O
80
94
Ph
O
CCl3
NH
Ph
N
CCl3
O
3
4
H
O
O
O
O
O
CCl3
NH
CCl3
N
CCl3
CCl3
2
3
4
5
75
87
H
7
8
O
O
N
82
80
80
84
H
9
10
MeO
MeO
NH
CCl3
O
O
N
CCl3
H
11
12
NH
CCl3
O
72c
67d
O
N
CCl3
CCl3
H
13
14
Cl
Cl
NH
CCl3
O
0 (32e)
85
O
N
6
7
0
H
15
16
O2N
O2N
NH
CCl3
O
O
N
H
CCl3
CCl3
56
55c
73
0g
17
19
18
20
Cl
NH
CCl3
Cl
O
O
N
H
8
59f
NH
CCl3
O
O
O
O
O
O
N
H
CCl3
9
62
21
22
Br
Br
NH
O
O
CCl3
N
CCl3
10
72
H
CbzN
23
NH
CbzN
24
O
11
12
25
47
15
13
BnO
CCl3
BnHN
CCl3
CCl3
25
NH
26
O
PMBHN
PMBO
CCl3
28
27
NH
O
O
CCl3
N
CCl3
13
0
0
H
29
30
O2N
O2N
b
aIsolated yield (%) from thermal conditions (nitromethane, reflux, 24 h) Isolated yield (%) from Lewis acid
d
catalyzed conditions (1 mol % BF3•OEt2, nitromethane, 0 °C 10 min). cReaction was performed for 72 h. Reaction
was performed for 24 h at rt. e10 mol % BF3•OEt2, nitromethane, reflux, 24 h. fReaction was performed for 1 h at rt.
gStarting material decomposed.
More complex substrates were also evaluated in the transformation (Table 3). A longer butyl
chain next to the benzylic imidate (31) gave a lower yield, probably for steric reasons, with an
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isopropyl substituent (32) reducing the isolated yield even further. Tethering the alkyl chain to
the benzene ring, as in the case of imidate 35 and imidate 37, provided reliable substrates for the
rearrangement. Subjecting diphenylmethyl imidate 1 to either rearrangement conditions gave the
trichloroacetamide product 2 in good yield. Adding a methoxy group at the ortho position in a
similar diphenylmethyl system (imidate 39) again gave lower yields, which may be attributed to
sterics. Interestingly, addition of a paraꢀnitro group to the DPM system (entry 7) did not slow the
rearrangement, and excellent yields of trichloroacetamide 42 were obtained under both thermal
and Lewis acid catalyzed conditions. Tertiary trichloroacetimidates were also briefly
investigated. tertꢀButyl trichloroacetimidate 43 gave very poor conversion under Lewis acid
catalyzed conditions, and no product was isolated from the thermal conditions. This may be
related to the high propensity of this imidate to eliminate.16 In contrast, the tertiary imidate 45
(entry 9),17 which cannot eliminate, provided a respectable yield of the rearranged product 46 but
only under thermal conditions, with the starting material decomposing under the Lewis acid
catalyzed conditions. Incorporation of a heteroatom next to the site of the imidate rearrangement
was also explored. Rearrangement of a protected glucose with an anomeric trichloroacetimidate
was successful, with imidate 47 undergoing rapid rearrangement under both thermal and Lewis
acid catalyzed conditions. Little preference for either anomer of the product was observed, with
the rearrangement providing a mixture of products in both cases. Incorporation of a nitrogen next
to the site of rearrangement was also investigated with phthalimidomethyl trichloroacetimidate
49 (entry 11). Like other primary trichloroacetimidates, this substrate was found to be less
reactive and had to be treated with 10% BF3•OEt2 at reflux for 48 hours to achieve
rearrangement. More highly substituted imidates with a neighboring nitrogen are reported to be
unstable, having to be prepared in situ and used immediately,18 and so these substrates were not
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pursued further. Rearrangement of ethyl trichloroacetimidate was also evaluated, but only trace
amounts of rearrangement were observed.
7
8
9
Table 3. Rearrangement of More Complex Imidates
MeNO2
R
NH
CCl3
R
O
reflux, 24 h or
Ar
O
Ar
N
H
CCl3
1 mol % BF3•OEt2
MeNO2, 0°C, 10 min
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
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38
39
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42
43
44
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49
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52
53
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5
6
entry
1
imidate
acetamide
yielda yieldb
O
NH
HN
CCl3
O
CCl3
63
16
72
56
41
74
32
31
Ph
Ph
Ph
O
NH
34
33
2
3
Ph
N
H
CCl3
O
CCl3
O
HN
36
35
CCl3
CCl3
N
O
HN
O
H
O
CCl3
37
CCl3
4
5
6
60
80
50
70
83
67
NH
O
38
Ph
Ph NH
Ph
N
CCl3
O
Ph
O
CCl3
1
H
2
MeO
Ph
MeO
Ph NH
N
CCl3
O
CCl3
H
40
39
Ph NH
Ph
O
O
CCl3
N
CCl3
7
8
9
74
88
H
41
42
O2N
O2N
O
NH
trace 8c
53
44
43
CCl3
N
H
CCl3
O
NH
O
H
Ph
Ph
O
N
CCl3
CCl3
0
O
O
N
N
46
45
Me
Me
H
O
O
CCl3
O
N
CCl3
BnO
BnO
BnO
10
42d 67e
NH
O
OBn
OBn
BnO
48
OBn
OBn
O
O
NH
O
11
12
0
0
29f
0
N
N
O
N
H
49
50
CCl3
CCl3
O
O
NH
O
51
52
EtO
CCl3
EtHN
CCl3
aIsolated yield (%) from thermal conditions (nitromethane, reflux, 24 h) Isolated yield (%) from Lewis acid
catalyzed conditions (1 mol % BF3•OEt2, nitromethane, 0 °C 10 min). c10 mol % BF3•OEt2, nitromethane, reflux 24
h. dIsolated as a 44:54 (α:β) mixture of anomers eIsolated as a 58:42 (α:β) mixture of anomers. f10 mol % BF3•OEt2,
nitromethane, reflux, 48 h.
b
The effect of the rearrangement on the stereochemistry of the substrate was also
investigated by subjecting nonracemic phenethyl trichloroacetimidate (S)ꢀ3 to the reaction
conditions (Scheme 2). In both cases (thermal and Lewis acid catalyzed), nearly complete
racemization was observed when the product of the reaction was analyzed by chiral HPLC.
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Scheme 2. Rearrangement of (S)-3
O
O
NH
5
6
7
10 mol %
BF3•OEt2
HN
Ph
CCl3
HN
Ph
CCl3
O CCl3
MeNO2
4 78%
<10% ee
reflux
21 h
4 83%
MeNO2
<10% ee 10 min
Ph
(S)-3
8
9
Given the observed racemization during the rearrangement and the substrate scope, an
analysis of the mechanism was undertaken. Two possibilities were considered: a concerted
bimolecular pathway (path A) or an ionization recombination pathway (path B) (Figure 1). The
poor yield with the ethyl imidate 51 and the success of the rearrangement of the hindered tertiary
trichloroacetimidate 45 led us to favor the cationic pathway, path B. This pathway is also
consistent with the observed racemization in Scheme 2, with the small deviation from completely
racemic product being attributed to memory of chirality from ion pair interactions.19 In the case
of the nitroꢀsubstituted diphenylmethyl trichloroacetimidate 41, the rearrangement may be
rationalized as the extended resonance effects of the two aromatic rings combined with the
inability to undergo elimination outweigh the electron withdrawing effect of the nitro group on
cation formation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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58
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H
N
Ph
NH
O
path A
H
CCl3
Cl3C
H
O
CCl3
N
H
O
Ph
A
Ph
3
path B
O
O
+
HN
Ph
CCl3
+
Ph
Cl3C
NH-
B
C
4
Figure 1. Possible Mechanisms for the Rearrangement
The benzylic trichloroacetamides provide ready access to both the corresponding
benzylic amine as well as other amineꢀbased functional groups such as carbamates and ureas. In
addition, it should be noted that trichloroacetamides are valuable precursors to nitrogen
containing heterocyclic systems via radical cyclizations.20 The amine may be accessed directly
by deprotection of the acetamide using sodium hydroxide,21 as shown for the deprotection of
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acetamide 8 below (Scheme 3). This provided the amine 53 in 58% yield. The trichloroacetamide
may also be directly converted to the corresponding carbamate,22 as heating acetamide 8 with
sodium methoxide in methanol gave the corresponding methyl carbamate 54 in 70% yield.
Additionally, the acetamide may be converted to the corresponding urea by the base promoted
addition of an amine.23 For example, subjecting acetamide 8 to Cs2CO3 and benzyl amine in
DMF provided urea 55 in 82% yield.
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Scheme 3. Further Transformations of Acetamide 8
O
NH2
NaOH
53 58%
MeOH/H2O
reflux, 18 h
O
O
O
O
O
O
O
MeONa
MeOH
reflux, 1 h
N
OMe
N
CCl3
H
H
54 70%
8
O
Cs2CO3
BnNH2
Bn
O
O
N
H
N
H
DMF, rt, 18 h
55 82%
In conclusion, conditions to facilitate the efficient rearrangement of benzylic
trichloroacetimidates to their corresponding trichloroacetamides have been developed. Use of
nitromethane as the reaction solvent is critical to achieve high conversion and avoid elimination.
The rearrangement occurred under both thermal conditions (in refluxing nitromethane) or in the
presence of Lewis acid catalysts like BF3•OEt2. Although some substrates decomposed under
one set of these conditions, typically they still underwent rearrangement using the alternative
protocol. Imidates that are precursors to stabilized carbocations gave the highest yields of the
rearranged products. Primary imidates tended to provide lower yields of the reaction products, as
the primary carbocation intermediate was more difficult to form. Increasing steric demands
around the site of rearrangement was detrimental to the yield of the transformation. These O to N
transpositions using trichloroacetimidates provide an entry to benzylic trichloroacetamides,
which are useful intermediates to access amines and a number of amine based functional groups
like carbamates and ureas.
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General: All anhydrous reactions were run under a positive pressure of argon or nitrogen.
Dichloromethane and THF were dried by passage through an alumina column following the
method of Grubbs.24 Column chromatography was performed using silica gel 60 (230−400
mesh). Melting points are uncorrected. NMR spectra were recorded in CDCl3, with residual
chloroform or TMS used as the internal reference. The trichloroacetimidates 1,25 3,26 11,27 17,15e
21,15e 25,28 27,29 29,30 37,15e 45,17 47,11b,31 and 4932 were prepared as previously described, while
tertꢀbutyl 2,2,2ꢀtrichloroacetimidate 43 and ethyl 2,2,2ꢀtrichloroacetimidate 51 were purchased
from commercial sources and used without further purification. The synthesis and analysis of the
enantiopurity of the chiral trichloroacetimidate (S)ꢀ3 was performed as previously reported.27
General Procedure for Synthesis of Trichloroacetimidates.
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The starting alcohol was dissolved in anhydrous DCM (0.25 M) under argon. DBU (10 mol %)
was then added. The mixture was stirred at room temperature for 15 min and then cooled to 0 °C.
Trichloroacetonitrile (1.2 equiv) was then added, and the reaction mixture was allowed to warm
to room temperature and stirred for 18 h. The reaction mixture was then concentrated and the
residue purified by silica gel chromatography (using the listed solvent system) to give the
trichloroacetimidate.
General Procedures for Rearrangement of Trichloroacetimidates to Trichloroacetamides.
Method A: Thermal Conditions
The imidate was dissolved in anhydrous nitromethane (1.0 M) under an argon atmosphere. The
resulting solution was heated to reflux for 24 h. The reaction mixture was then allowed to cool to
room temperature and the solvent was removed in vacuo. The residue was purified by silica gel
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chromatography (using the listed solvent system) to provide the corresponding
trichloroacetamide product.
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Method B: Lewis Acid Catalyzed Conditions
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The imidate was dissolved in anhydrous nitromethane (0.25 M) under an argon atmosphere. The
solution was cooled to 0 °C and BF3•OEt2 (1 mol %) was added. The resulting solution was then
stirred at 0 °C for the listed amount of time. The mixture was then quenched by the addition of
sat. aq. sodium bicarbonate. The resulting suspension was then extracted with DCM (3x). The
combined extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by
silica gel chromatography (using the listed solvent system) to provide the pure
trichloroacetamide product.
N-Benzhydryl-trichloroacetamide (2).15a Prepared using method A (0.16 g, 80%) and method
B (0.25 g, 83%), purified using silica gel chromatography (5% ethyl acetate/94% hexanes/1%
triethylamine). White solid; mp = 121ꢀ123 °C; TLC Rf = 0.65 (10% ethyl acetate/90% hexanes);
1H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.31 (m, 6H), 7.26ꢀ7.25 (m, 4H), 7.16 (d, J = 6.4 Hz, 1H),
6.18 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.9, 139.8, 129.0, 128.2, 127.4, 92.7,
59.0.
2,2,2-Trichloro-N-(1-phenylethyl)acetamide (4).26 Prepared using method A (0.12 g, 80%) and
method B (0.24 g, 94%), purified using silica gel chromatography (10% ethyl acetate/89%
hexanes/1% triethylamine). White solid; mp = 117ꢀ119 °C; TLC Rf = 0.33 (10% ethyl
1
acetate/90% hexanes); IR (thin film) 3310, 3064, 2991, 1681, 1519 cmꢀ1; H NMR (300 MHz,
CDCl3) δ 7.39ꢀ7.28 (m, 5H), 6.92 (br s, 1H), 5.07 (p, J = 7.2 Hz, 1H), 1.59 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 161.0, 141.4, 129.0, 128.0, 126.1, 92.7, 51.1, 21.2. Chiral HPLC
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analysis: Chiralcel OJ (heptane/iꢀPrOH = 50/50, 0.5 mL/min, 254 nm, 25 °C): t1 = 11.1 min, t2 =
12.7 min.
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N-(1-(Benzo[d][1,3]dioxol-6-yl)ethyl)-2,2,2-trichloroacetimidate (7). Prepared using the
general procedure for synthesis of trichloroacetimidates and purified using silica gel
chromatography (10% ethyl acetate/89% hexanes/1% triethylamine). White solid (3.10 g, 75%);
mp = 39ꢀ42 °C; TLC Rf = 0.69 (10% ethyl acetate/90% hexanes); IR (thin film) 3338, 2982,
2932, 2892, 1661 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.30 (br s, 1H), 6.93 (d, J = 1.2 Hz, 1H),
6.88 (dd, J = 8.0, 1.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.95 (s, 2H), 5.90 (q, J = 6.4 Hz, 1H),
1.61 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 147.8, 147.3, 135.2, 119.6,
108.2, 106.6, 101.1, 91.8, 77.0, 22.2. Anal. Calcd for C11H10Cl3NO3: C, 42.54; H, 3.25; N, 4.51;
Found: C, 42.35; H, 3.17; N, 4.52.
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N-(1-(Benzo[d][1,3]dioxol-6-yl)ethyl)-2,2,2-trichloroacetamide (8). Prepared using method A
(0.23 g, 75%) and method B (0.13 g, 87%), purified using silica gel chromatography (10% ethyl
acetate/89% hexanes/1% triethylamine). White solid; mp = 112ꢀ115 °C; TLC Rf = 0.23 (10%
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ethyl acetate/90% hexanes); IR (thin film) 3307, 2997, 2957, 2897, 1682 cmꢀ1; H NMR (400
MHz, CDCl3) δ 6.83ꢀ6.75 (m, 4H), 5.97 (s, 2H), 4.99 (p, J = 6.8 Hz, 1H), 1.57 (d, J = 6.8 Hz,
3H) ; 13C NMR (100 MHz, CDCl3) δ 160.9, 148.1, 147.3, 135.2, 119.5, 108.5, 106.7, 101.3,
92.7, 51.0, 21.2; Anal. Calcd for C11H10Cl3NO3: C, 42.54; H, 3.25; N, 4.51; Found: C, 42.54; H,
3.25; N, 4.52.
2,2,2-Trichloro-N-(1-(4-methoxyphenyl)ethyl)acetimidate (9). Prepared using the general
procedure for synthesis of trichloroacetimidates, purified using silica gel chromatography (10%
ethyl acetate/89% hexanes/1% triethylamine). White solid (1.14 g, 53%); mp = 59ꢀ68 °C; TLC
Rf = 0.66 (10% ethyl acetate/90% hexanes); IR (thin film) 3337, 3059, 2986, 2934, 1685, 1660,
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1513 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.28 (br s, 1H), 7.36 (dd, J = 6.4, 1.6 Hz, 2H), 6.90ꢀ
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6.87 (m, 2H), 5.94 (q, J = 6.4 Hz, 1H), 3.80 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H); C NMR (100
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MHz, CDCl3) δ 161.6, 159.3, 133.3, 127.3, 113.8, 91.8, 76.9, 55.2, 22.0; Anal. Calcd for
C11H12Cl3NO2: C, 44.55; H, 4.08; N, 4.72; Found: C, 44.88; H, 4.13; N, 4.68.
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2,2,2-Trichloro-N-(1-(4-methoxyphenyl)ethyl)acetamide (10). Prepared using method A (0.25
g, 82%) and method B (0.12 g, 80%), purified using silica gel chromatography (5% ethyl
acetate/94% hexanes/1% triethylamine). White solid; mp = 89ꢀ91 °C; TLC Rf = 0.25 (10% ethyl
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acetate/90% hexanes); IR (thin film) 3329, 2977, 2934, 2836, 1660, 1585, 1513 cmꢀ1; H NMR
(400 MHz, CDCl3) δ 7.28ꢀ7.26 (m, 2H), 6.92ꢀ6.90 (m, 2H), 6.75 (br s, 1H), 5.04 (p, J = 7.2 Hz,
1H), 3.81 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.9, 159.3, 133.4,
127.4, 114.3, 92.8, 55.3, 50.6, 21.0; Anal. Calcd for C11H12Cl3NO2: C, 44.55; H, 4.08; N, 4.72;
Found: C, 44.68; H, 4.24; N, 4.76.
2,2,2-Trichloro-N-(1-p-tolylethyl)acetamide (12). Prepared using method A (0.24 g, 82%,
purified using silica gel chromatography with 2% ethyl acetate/98% toluene) and method B
(0.084 g, 84%, purified using silica gel chromatography with 5% ethyl acetate/95% hexanes).
Yellow solid; mp = 74ꢀ77 °C; TLC Rf = 0.44 (10% ethyl acetate/90% hexanes); IR (thin film)
3322, 3026, 2980, 2927, 2873, 1697 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.25ꢀ7.18 (m, 4H), 6.78
(br s, 1H), 5.05 (p, J = 7.2 Hz, 1H), 2.35 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.9, 138.5, 138.4, 137.7, 129.6, 126.1, 92.8, 51.0, 21.1; Anal. Calcd for
C11H12Cl3NO: C, 47.09; H, 4.31; N, 4.99; Found: C, 46.69; H, 4.38; N, 4.99.
2,2,2-Trichloro-N-(1-(4-chlorophenyl)ethyl)acetimidate (13). Prepared using the general
procedure for synthesis of trichloroacetimidates and purified using silica gel chromatography
(10% ethyl acetate/89% hexanes/1% triethylamine). White solid (2.40 g, 79%); mp = 39ꢀ41 °C;
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TLC Rf = 0.47 (10% ethyl acetate/90% hexanes); IR (thin film) 3341, 2983, 2933, 1663, 1375
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.32 (br s, 1H), 7.37ꢀ7.32 (m, 4H), 5.95 (q, J = 6.8 Hz, 1H),
1.63 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 139.9, 133.7, 128.7, 127.3, 91.6,
76.4, 22.2; Anal. Calcd for C10H9Cl4NO: C, 39.90; H, 3.01; N, 4.65; Found: C, 39.66; H, 3.31;
N, 4.55.
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2,2,2-Trichloro-N-(1-(4-chlorophenyl)ethyl)acetamide (14). Prepared using method A (0.22 g,
72%) and using a modified method B where the reaction was allowed to proceed for 1 h (0.10 g,
67%), purified using silica gel chromatography (10% ethyl acetate/89% hexanes/1%
triethylamine). White solid; mp = 92ꢀ94 °C; TLC Rf = 0.33 (10% ethyl acetate/90% hexanes); IR
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(thin film) 3326, 3029, 2981, 2934, 1695, 1577 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.37ꢀ7.26
(m, 4H), 6.79 (br s, 1H), 5.05 (p, J = 6.8 Hz, 1H), 1.59 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.0, 140.0, 133.7, 129.1, 127.5, 92.6, 50.6, 21.2; Anal. Calcd for C10H9Cl4NO: C,
39.90; H, 3.01; N, 4.65; Found: C, 40.16; H, 3.25; N, 4.59.
2,2,2-Trichloro-N-(1-(4-nitrophenyl)ethyl)acetimidate (15). Prepared using the general
procedure for synthesis of trichloroacetimidates and purified using silica gel chromatography
(15% ethyl acetate/83% hexanes/2% triethylamine).White solid (1.80 g, 97%); mp = 56ꢀ59 °C;
TLC Rf = 0.58 (30% ethyl acetate/70% hexanes); IR (thin film) 3340, 3083, 2987, 2936, 1666,
1605 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.38 (br s, 1H), 8.24 (d, J = 8.8 Hz, 2H), 7.59 (d, J =
13
8.8 Hz, 2H), 6.05 (q, J = 6.8 Hz, 1H), 1.68 (d, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ
161.3, 148.6, 147.5, 126.6, 123.9, 91.3, 75.9, 22.1; Anal. Calcd for C10H9Cl3N2O3: C, 38.55; H,
2.91; N, 8.99; Found: C, 38.61; H, 2.92; N, 8.97.
2,2,2-Trichloro-N-(1-(4-nitrophenyl)ethyl)acetamide (16). Prepared using a modified method
B (0.065g, 32%) where 10 mol % BF3•OEt2 was used and the reaction was heated to reflux for
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24 h. Purified using silica gel chromatography (5% ethyl acetate/94% hexanes/1%
triethylamine). White solid; mp = 118ꢀ126 °C; TLC Rf = 0.35 (30% ethyl acetate/ 70% hexanes);
IR (thin film) 3341, 2983, 2931, 1699, 1604 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.4
Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 4.4 Hz, 1H), 5.14 (p, J = 6.8 Hz, 1H), 1.65 (d, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.3, 148.8, 147.5, 126.9, 124.2, 92.3, 50.8, 21.5;
Anal. Calcd for C10H9Cl3N2O3: C, 38.55; H, 2.91; N, 8.99; Found: C, 38.57; H, 2.85; N, 9.25.
2,2,2-Trichloro-N-(1-o-tolylethyl)acetamide (18). Prepared using method A (0.15 g, 56%) and
method B (0.085 g, 85%), purified using silica gel chromatography (10% ethyl acetate/90%
hexanes). White solid; mp = 116ꢀ120 °C; TLC Rf = 0.42 (10% ethyl acetate/90% hexanes); IR
(thin film) 3335, 3053, 3025, 2979, 2933, 2873, 1695 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.33ꢀ
7.19 (m, 4H), 6.79 (br s, 1H), 5.25 (p, J = 6.8 Hz, 1H), 2.39 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.8, 139.2, 136.1, 131.0, 128.0, 126.6, 124.6, 92.7, 47.9, 20.4,
19.1. Anal. Calcd for C11H12Cl3NO: C, 47.09; H, 4.31; N, 4.99; Found: C, 46.96; H, 4.22; N,
4.84.
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2,2,2-Trichloro-N-(1-(2-chlorophenyl)ethyl)acetimidate (19). Prepared using the general
procedure for synthesis of trichloroacetimidates and purified using silica gel chromatography
(5% ethyl acetate/94% hexanes/1% triethylamine). Colorless oil (1.04 g, 86%); TLC Rf = 0.63
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(10% ethyl acetate/90% hexanes); H NMR (400 MHz, CDCl3) δ 8.35 (br s, 1H), 7.57 (dd, J =
7.6, 1.6 Hz, 1H), 7.36 (dd, J = 7.6, 1.6 Hz, 1H), 7.31ꢀ7.21 (m, 2H), 6.31 (q, J = 6.4 Hz, 1H), 1.64
(d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.2, 139.4, 131.7, 129.5, 128.9, 127.3,
126.2, 91.6, 74.1, 20.9; Anal. Calcd for C10H9Cl4NO: C, 39.90; H, 3.01; N, 4.65; Found: C,
39.70; H, 2.95; N, 4.51.
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2,2,2-Trichloro-N-(1-(2-chlorophenyl)ethyl)acetamide (20). Prepared using a modified
method A where the reaction was refluxed for 72 h (0.11 g, 55%) and using a modified method B
where the reaction was allowed to proceed for 1 h (0.080 g, 59%), purified using silica gel
chromatography (10% ethyl acetate/89% hexanes/1% triethylamine). White solid; mp = 127ꢀ128
°C; TLC Rf = 0.32 (10% ethyl acetate/90% hexanes); IR (thin film) 3297, 3030, 2982, 2933,
1691, 1520 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.41ꢀ7.24 (m, 4H), 7.10 (br s, 1H), 5.35 (p, J =
6.8 Hz, 1H), 1.62 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8, 138.6, 132.9, 130.4,
129.1, 127.4, 127.2, 92.6, 49.6, 20.3; Anal. Calcd for C10H9Cl4NO: C, 39.90; H, 3.01; N, 4.65;
Found: C, 40.04; H, 3.01; N, 4.97.
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N-(1-(5-Bromobenzo[d][1,3]dioxol-6-yl)ethyl)-2,2,2-trichloroacetamide (22). Prepared using
method A (0.15 g, 73%) and method B (0.16 g, 62%), purified using silica gel chromatography
(10% ethyl acetate/89% hexanes/1% triethylamine). White solid; mp = 139ꢀ141 °C; TLC Rf =
1
0.62 (30% ethyl acetate/70% hexanes); IR (thin film) 3327, 2981, 2899, 1694 cmꢀ1; H NMR
(400 MHz, CDCl3) δ 7.03 (s, 1H), 6.92 (s, 1H), 6.82 (s, 1H), 5.99 (q, J = 1.2 Hz, 2H), 5.23 (p, J
= 7.2 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.7, 148.0, 147.9,
133.4, 113.6, 113.4, 106.8, 102.0, 92.5, 51.3, 20.4; Anal. Calcd for C11H9BrCl3NO3: C, 33.92; H,
2.33; N, 3.60; Found: C, 33.67; H, 2.45; N, 3.83.
Benzyl 3-(1-(2,2,2-trichloroacetimido)ethyl)-1H-indole-1-carboxylate (23). Prepared using
the general procedure for synthesis of trichloroacetimidates and purified using silica gel
chromatography (10% ethyl acetate/89% hexanes/1% triethylamine). White solid (1.47 g, 76%);
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mp = 78ꢀ85 °C; IR (thin film) 3338, 3089, 3034, 2982, 2936, 1740, 1662 cmꢀ1; H NMR (400
MHz, CDCl3) δ 8.40 (s, 1H), 8.18 (d, J = 5.6 Hz, 1H), 7.68ꢀ7.67 (m, 2H), 7.50ꢀ7.22 (m, 7H),
6.31 (q, J = 6.4 Hz, 1H), 5.44ꢀ5.37 (m, 2H), 1.77 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
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CDCl3) δ 161.8, 150.8, 135.9, 135.1, 128.9, 128.6, 128.4, 127.8, 125.1, 123.2, 123.0, 121.6,
120.2, 115.5, 91.9, 71.2, 68.9, 19.8; Anal. Calcd for C20H17Cl3N2O3: C, 54.63; H, 3.90; N, 6.37;
Found: C, 54.70; H, 3.92; N, 6.24.
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Benzyl 3-(1-(2,2,2-trichloroacetamido)ethyl)-1H-indole-1-carboxylate (24). Prepared using
method B (0.072 g, 72%), purified using silica gel chromatography (10% ethyl acetate/90%
hexanes). White solid; mp = 126ꢀ128 °C; TLC Rf = 0.53 (25% ethyl acetate/75% hexanes); IR
(thin film) 3333, 3065, 3031, 2979, 2936, 1734, 1703, 1608 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ
8.18 (d, J = 6.8 Hz, 1H), 7.62 (s, 1H), 7.58ꢀ7.55 (m, 1H), 7.50ꢀ7.47 (m, 2H), 7.45ꢀ7.34 (m, 4H),
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7.30ꢀ7.27 (m, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.50ꢀ5.34 (m, 3H), 1.71 (d, J = 6.8 Hz, 3H); C
NMR (100 MHz, CDCl3) δ 161.1, 150.7, 135.9, 134.9, 128.90, 128.85, 128.61, 128.56, 125.4,
123.5, 122.7, 121.9, 119.4, 115.5, 92.7, 69.0, 43.9, 19.4; Anal. Calcd for C20H17Cl3N2O3: C,
54.63; H, 3.90; N, 6.37; Found: C, 54.67; H, 3.92; N, 6.50.
N-Benzyl-2,2,2-trichloroacetamide (26).33 Prepared using method A (0.050 g, 25%) and
method B (0.015 g, 15%), purified using silica gel chromatography (10% ethyl acetate/89%
hexanes/1% triethylamine). White solid; mp = 87ꢀ92 °C; TLC Rf = 0.50 (20% ethyl acetate/ 80%
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.30 (m, 5H), 7.00 (br s, 1H), 4.55 (d, J = 5.6 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 161.9, 136.3, 129.0, 128.2, 127.8, 92.6, 45.4.
N-(4-Methoxybenzyl)-2,2,2-trichloroacetamide (28). Prepared using method A (0.070 g, 47%)
and method B (0.013 g, 13%), purified using silica gel chromatography (10% ethyl acetate/89%
hexanes/1% triethylamine). White solid; mp = 95ꢀ100 °C; TLC Rf = 0.18 (10% ethyl
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acetate/90% hexanes); IR (thin film) 3313, 3044, 3002, 2954, 1692, 1613 cmꢀ1; H NMR (400
MHz, CDCl3) δ 7.26ꢀ7.24 (m, 2H), 6.92ꢀ6.84 (m, 3H), 4.49 (d, J = 5.6 Hz, 2H), 3.81 (s, 3H); 13C
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NMR (100 MHz, CDCl3) δ 161.8, 159.5, 129.3, 128.4, 114.4, 92.6, 55.3, 44.9; Anal. Calcd for
C10H10Cl3NO2: C, 42.51; H, 3.57; N, 4.96; Found: C, 42.72; H, 3.77; N, 5.22.
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2,2,2-Trichloro-N-(1-phenylpentyl)acetimidate (31). Prepared using the general procedure for
synthesis of trichloroacetimidates and purified using silica gel chromatography (8% ethyl
acetate/90% hexanes/2% triethylamine). Yellow oil (1.69 g, 96%); TLC Rf = 0.71 (10% ethyl
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acetate/90% hexanes); IR (thin film) 3348, 3092, 3069, 3036, 2958, 2934, 2863, 1659 cmꢀ1; H
NMR (400 MHz, CDCl3) δ 8.23 (br s, 1H), 7.41ꢀ7.27 (m, 5H), 5.81 (q, J = 5.6 Hz, 1H), 2.09ꢀ
2.00 (m, 1H), 1.89ꢀ1.80 (m, 1H), 1.50ꢀ1.41 (m, 1H), 1.38ꢀ1.30 (m, 3H), 0.89 (t, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 161.7, 140.6, 128.4, 127.9, 126.2, 91.9, 81.0, 36.7, 27.7, 22.5,
14.1; Anal. Calcd for C13H16Cl3NO: C, 50.59; H, 5.23; N, 4.54; Found: C, 50.32; H, 5.36; N,
4.42.
2,2,2-Trichloro-N-(1-phenylpentyl)acetamide (32). Prepared using method A (0.19 g, 63%)
and method B (0.084 g, 56%), purified using silica gel chromatography (5% ethyl acetate/95%
hexanes). White solid; mp = 57ꢀ61 °C; TLC Rf = 0.49 (10% ethyl acetate/90% hexanes); IR (thin
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film) 3431, 3067, 3033, 2957, 2931, 2861, 1698 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.29
(m, 5H), 6.81 (br s, 1H), 4.90 (q, J = 7.6 Hz, 1H), 1.94ꢀ1.87 (m, 2H), 1.39ꢀ1.24 (m, 4H), 0.89 (t,
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J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ 161.1, 140.7, 128.9, 127.9, 126.5, 92.9, 55.8,
35.6, 28.3, 22.4, 14.0; Anal. Calcd for C13H16Cl3NO: C, 50.59; H, 5.23; N, 4.54; Found: C,
50.49; H, 5.18; N, 4.79.
2,2,2-Trichloro-N-(2-methyl-1-phenylpropyl)acetimidate (33). Prepared using the general
procedure for synthesis of trichloroacetimidates and purified using silica gel chromatography
(5% ethyl acetate/93% hexanes/2% triethylamine). Colorless oil (3.01 g, 86%); TLC Rf = 0.63
(10% ethyl acetate/ 90% hexanes); IR (thin film) 3339, 3088, 3062, 3032, 2979, 2961, 2925,
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2868, 1660 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.23 (br s, 1H), 7.41ꢀ7.28 (m, 5H), 5.57 (d, J =
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7.2 Hz, 1H), 2.29ꢀ2.17 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H); C NMR
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(100 MHz, CDCl3) δ 161.7, 139.1, 128.2, 127.9, 126.9, 92.0, 85.8, 34.4, 19.0, 18.4; Anal. Calcd
for C12H14Cl3NO: C, 48.92; H, 4.79; N, 4.75; Found: C, 48.72; H, 4.42; N, 4.64.
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2,2,2-Trichloro-N-(2-methyl-1-phenylpropyl)acetamide (34). Prepared using method A (0.049
g, 16%) and method B (0.062 g, 41%), purified using silica gel chromatography (1% ethyl
acetate/99% toluene). White solid; mp = 78ꢀ82 °C; TLC Rf = 0.38 (10% ethyl acetate/ 90%
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hexanes); IR (thin film) 3338, 3066, 3033, 2963, 2934, 2873, 1693, 1515 cmꢀ1; H NMR (400
MHz, CDCl3) δ 7.38ꢀ7.34 (m, 2H), 7.31ꢀ7.24 (m, 3H), 6.96 (d, J = 6.8 Hz, 1H), 4.69 (t, J = 8.4
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Hz, 1H), 2.23ꢀ2.11 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H); C NMR (100
MHz, CDCl3) δ 161.1, 139.7, 128.7, 127.8, 126.7, 93.0, 61.4, 33.6, 19.7, 18.5; Anal. Calcd for
C12H14Cl3NO: C, 48.92; H, 4.79; N, 4.75; Found: C, 48.96; H, 4.86; N, 4.87.
2,2,2-Trichloro-N-(2,3-dihydro-1H-inden-3-yl)acetimidate (35). Prepared using the general
procedure for synthesis of trichloroacetimidates and purified using silica gel chromatography
(10% ethyl acetate/89% hexanes/1% triethylamine). Clear colorless oil (0.73 g, 86%); TLC Rf =
1
0.85 (10% ethyl acetate/90% hexanes); IR (thin film) 3340, 3028, 2943, 2852, 1660 cmꢀ1; H
NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.34ꢀ7.22 (m, 3H), 6.35 (q, J =
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2.8 Hz, 1H), 3.19ꢀ3.11 (m, 1H), 2.96ꢀ2.89 (m, 1H), 2.67ꢀ2.58 (m, 1H), 2.27ꢀ2.19 (m, 1H); C
NMR (100 MHz, CDCl3) δ 162.8, 144.5, 140.6, 129.2, 126.8, 125.7, 124.9, 91.9, 83.3, 32.0,
30.2; Anal. Calcd for C11H10Cl3NO: C, 47.43; H, 3.62; N, 5.03; Found: C, 47.15; H, 3.95; N,
5.27.
2,2,2-Trichloro-N-(2,3-dihydro-1H-inden-3-yl)acetamide (36). Prepared using method A
(0.072 g, 72%) and method B (0.074 g, 74%), purified using silica gel chromatography (5% ethyl
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acetate/94% hexanes/1% triethylamine). White solid; mp = 86ꢀ89 °C; TLC Rf = 0.51 (10% ethyl
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acetate/90% hexanes); IR (thin film) 3319, 3024, 2944, 2850, 1692, 1518 cmꢀ1; H NMR (400
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MHz, CDCl3) δ 7.26ꢀ7.16 (m, 4H), 6.74 (s, 1H), 5.39 (q, J = 7.6 Hz, 1H), 3.02ꢀ2.95 (m, 1H),
2.91ꢀ2.83 (m, 1H), 2.66ꢀ2.58 (m, 1H), 1.91ꢀ1.82 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 161.8,
143.5, 141.5, 128.7, 127.2, 125.1, 124.0, 92.7, 56.8, 33.4, 30.3; Anal. Calcd for C11H10Cl3NO: C,
47.43; H, 3.62; N, 5.03; Found: C, 47.09; H, 3.90; N, 4.95.
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2,2,2-Trichloro-N-(1,2,3,4-tetrahydronaphthalen-4-yl)acetamide (38). Prepared using method
A (0.13 g, 60%) and method B (0.11 g, 70%), purified using silica gel chromatography (10%
ethyl acetate/89% hexanes/1% triethylamine). White solid; mp = 129ꢀ130 °C; TLC Rf = 0.33
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(10% ethyl acetate/90% hexanes); IR (thin film) 3285, 3057, 2920, 2864, 1691, 1536 cmꢀ1; H
NMR (400 MHz, CDCl3) δ 7.28ꢀ7.14 (m, 4H), 6.80 (br s, 1H), 5.17ꢀ5.12 ( m, 1H), 2.90ꢀ2.76 (m,
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2H), 2.18ꢀ2.10 (m, 1H), 1.96ꢀ1.84 (m, 3H); C NMR (100 MHz, CDCl3) δ 161.3, 137.7, 134.9,
129.5, 128.5, 128.0, 126.7, 92.9, 49.9, 29.4, 29.1, 19.9; Anal. Calcd for C12H12Cl3NO: C, 49.26;
H, 4.13; N, 4.79; Found: C, 48.97; H, 4.13; N, 4.86.
2,2,2-Trichloro-N-((2-methoxyphenyl)(phenyl)methyl)acetimidate (39). Prepared using the
general procedure for synthesis of trichloroacetimidates and purified using silica gel
chromatography (5% ethyl acetate/94% hexanes/1% triethylamine). White solid (2.76 g, 81%);
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mp = 93ꢀ96 °C; IR (thin film) 3337, 3064, 3032, 3005, 2960, 2938, 1665, 1601 cmꢀ1; H NMR
(400 MHz, CDCl3) δ 8.36 (s, 1H), 7.50ꢀ7.46 (m, 3H), 7.35ꢀ7.25 (m, 5H), 6.97 (td, J = 7.6, 0.8
Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.3, 156.4,
139.7, 129.1, 128.5, 128.3, 127.8, 127.0, 126.8, 120.7, 110.7, 91.7, 76.2, 55.6; Anal. Calcd for
C16H14Cl3NO2: C, 53.58; H, 3.93; N, 3.91; Found: C, 53.54; H, 3.82; N, 3.97.
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2,2,2-Trichloro-N-((2-methoxyphenyl)(phenyl)methyl)acetamide (40). Prepared using
method A (0.072 g, 50%) and method B (0.100 g, 67%), purified using silica gel
chromatography (5% ethyl acetate/95% hexanes). White solid; mp = 109ꢀ112 °C; TLC Rf = 0.34
(10% ethyl acetate/90% hexanes); IR (thin film) 3404, 3062, 3028, 2936, 2838, 1714, 1601 cmꢀ1;
1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.0 Hz, 1H), 7.37ꢀ7.20 (m, 7H), 7.01 (t, J = 7.6 Hz,
1H), 6.96 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.0, 157.1, 140.1, 129.8, 129.6, 128.5, 127.4, 127.1, 126.4, 121.2, 111.7, 93.1, 56.8,
55.6; Anal. Calcd for C16H14Cl3NO2: C, 53.58; H, 3.93; N, 3.91; Found: C, 53.86; H, 3.83; N,
3.83.
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2,2,2-Trichloro-N-((4-nitrophenyl)(phenyl)methyl)acetimidate (41). Prepared using the
general procedure for synthesis of trichloroacetimidates and purified using silica gel
chromatography (10% hexanes/88% toluene/2% triethylamine). White solid (1.34 g, 86%); mp =
89ꢀ93 °C; TLC Rf = 0.62 (30% ethyl acetate/ 70% hexanes); IR (thin film) 3339, 3039, 1667,
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1606, 1523 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.50 (br s, 1H), 8.21 (d, J = 8.8 Hz, 2H), 7.62
(d, J = 8.8 Hz, 2H), 7.43ꢀ7.32 (m, 5H), 7.00 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 161.0,
147.6, 146.9, 138.3, 128.9, 128.7, 127.6, 127.1, 123.9, 91.2, 80.3; Anal. Calcd for
C15H11Cl3N2O3: C, 48.22; H, 2.97; N, 7.50; Found: C, 48.09; H, 2.97; N, 7.33.
2,2,2-Trichloro-N-((4-nitrophenyl)(phenyl)methyl)acetamide (42). Prepared using method A
(0.149 g, 74%) and method B (0.088 g, 88%), purified using silica gel chromatography (10%
ethyl acetate/90% hexanes). White solid; mp = 145ꢀ148 °C; TLC Rf = 0.29 (20% ethyl acetate/
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80% hexanes); IR (thin film) 3280, 3064, 1702, 1606 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.22
(d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.43ꢀ7.36 (m, 3H), 7.26ꢀ7.22 (m, 3H), 6.22 (d, J =
7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 161.2, 147.6, 146.9, 138.4, 129.5, 129.0, 127.9,
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127.6, 124.2, 92.2, 58.7; Anal. Calcd for C15H11Cl3N2O3: C, 48.22; H, 2.97; N, 7.50; Found: C,
48.23; H, 3.07; N, 7.49.
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N-tert-Butyl-2,2,2-trichloroacetamide (44).34 Pink solid (0.012 g, 8%); TLC Rf = 0.40 (15%
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ethyl acetate/ 85% hexanes); H NMR (400 MHz, CDCl3) δ 6.48 (br s, 1H), 1.43 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 160.4, 93.3, 53.0, 28.1.
2,2,2-Trichloro-N-(1-methyl-2-oxo-3-phenylindolin-3-yl)acetamide (46). Prepared using
method A (0.047 g, 47%), purified using silica gel chromatography (20% ethyl acetate/88%
hexanes/2% triethylamine). White solid; mp = 197ꢀ205 °C; TLC Rf = 0.21 (20% ethyl
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acetate/80% hexanes); H NMR (400 MHz, CDCl3) δ 7.39ꢀ7.31 (m, 8H), 7.11 (td, J = 7.6, 0.8
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Hz, 1H), 6.87 (d, 7.6 Hz, 1H), 3.17 (s, 3H); C NMR (100 MHz, CDCl3) δ 173.6, 160.5, 144.6,
136.5, 130.2, 129.5, 129.3, 127.2, 126.7, 124.8, 123.2, 108.9, 91.8, 65.1, 27.0; Anal. Calcd for
C17H13Cl3N2O2: C, 53.22; H, 3.42; N, 7.30; Found: C, 53.40; H, 3.43; N, 7.28.
N-((2S,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)methyl)-tetrahydro-2H-pyran-2-
yl)-2,2,2-trichloroacetamide (48a) and N-((2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-
((benzyloxy)methyl)-tetrahydro-2H-pyran-2-yl)-2,2,2-trichloroacetamide
(48b).
Rearrangement of imidate 47 using method A provided 48a (0.040 g, 21%) and 48b (0.040g,
21%) after purification with silica gel chromatography (10% ethyl acetate/90% hexanes). This
rearrangement was also successful with method B, providing 48a (0.047 g, 47%) and 48b
(0.020g, 20%) after purification with silica gel chromatography (10% ethyl acetate/90%
hexanes).
48a.11b Colorless oil (0.04 g, 21%); TLC Rf = 0.38 (20% ethyl acetate/80% hexanes); H NMR
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(400 MHz, CDCl3) δ 7.33ꢀ7.24 (m, 19H), 7.15ꢀ7.12 (m, 2H), 5.60 (t, J = 5.6 Hz, 1H), 4.91 (d, J
= 10.8 Hz, 1H), 4.79 (t, J = 11.2 Hz, 2H), 4.65ꢀ4.57 (m, 3H), 4.54ꢀ4.47 (m, 2H), 3.89ꢀ3.86 (m,
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1H), 3.80ꢀ3.76 (m, 2H), 3.69ꢀ3.64 (m, 3H); C NMR (100 MHz, CDCl3) δ 162.2, 138.2, 137.9,
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137.8, 136.9, 128.7, 128.51, 128.50, 128.43, 128.39, 128.2, 128.1, 128.04, 127.98, 127.9, 127.8,
92.4, 81.6, 77.0, 76.5, 75.5, 75.2, 73.6, 73.0, 71.9, 68.1.
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48b.11b White solid (0.04 g, 21%); mp = 121ꢀ126 °C; TLC Rf = 0.32 (20% ethyl acetate/80%
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hexanes); IR (thin film) 3325, 3064, 3031, 2924, 2858, 1706, 1520 cmꢀ1; H NMR (400 MHz,
CDCl3) δ 7.37ꢀ7.25 (m, 18H), 7.14ꢀ7.12 (m, 2H), 6.98 (d, J = 8.8 Hz, 1H), 5.08 (t, J = 9.2 Hz,
1H), 4.89 (s, 2H), 4.83ꢀ72 (m, 3H), 4.61 (d, J = 12.4 Hz, 1H), 4.51 (dd, J = 20.4, 10.8 Hz, 2H),
3.80ꢀ3.69 (m, 4H), 3.56ꢀ3.46 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.7, 138.2, 137.9, 137.6,
137.4, 128.7, 128.52, 128.47, 128.46, 128.44, 128.2, 128.1, 127.90, 127.85, 92.2, 85.8, 81.0,
79.8, 77.3, 76.9, 75.7, 75.0, 74.8, 73.6, 67.9; Anal. Calcd for C36H36Cl3NO6: C, 63.12; H, 5.30;
N, 2.04; Found: C, 63.19; H, 5.37; N, 2.06.
2,2,2-Trichloro-N-((1,3-dioxoisoindolin-2-yl)methyl)acetamide (50). Prepared using
a
modified method B (0.058 g, 29%) where the reaction was performed with 10 mol % BF3•OEt2
at rt for 48 h, purified using silica gel chromatography (1% ethyl acetate/99% dichloromethane).
White solid; mp = 218ꢀ223 °C; TLC Rf = 0.71 (2% ethyl acetate/ 98% dichloromethane); IR
(thin film) 3317, 3123, 1709, 1514 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.93ꢀ7.89 (m, 2H), 7.80ꢀ
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7.76 (m, 2H), 7.52 (br s, 1H), 5.31 (d, J = 6.4 Hz, 2H); C NMR (100 MHz, CDCl3) δ 167.1,
161.6, 134.6, 131.7, 123.9, 92.0, 44.0; Anal. Calcd for C11H7Cl3N2O3: C, 41.09; H, 2.19; N, 8.71;
Found: C, 41.04; H, 2.21; N, 8.74.
1-(Benzo[d][1,3]dioxol-6-yl)ethanamine (53).35 To the solution of amide 8 (0.10 g, 0.32 mmol)
in 2.1 mL methanol, solution of sodium hydroxide (0.051 g in 0.5 mL water) was added and the
reaction mixture was heated to reflux for 18 h. Then the mixture was cooled to room temperature
and concentrated. The residue was partitioned between 10 mL water and 5 mL DCM. The
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organic layer was separated and the aqueous layer was extracted with DCM twice (2 x 5 mL).
The combined organic layers were dried over sodium sulfate and then filtered and concentrated
to provide crude amine 53. The crude residue was then purified by silica gel chromatography
(1% triethylamine/ 2% methanol/ 97% dichloromethane) to provide the pure amine 53 (0.031 g,
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58%). H NMR (400 MHz, CDCl3) δ 6.89 (d, J = 1.6 Hz, 1H), 6.82ꢀ6.74 (m, 2H), 5.94 (s, 2H),
4.09 (q, J = 6.8 Hz, 1H), 2.86 (br s, 2H), 1.39 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 147.8, 146.4, 141.1, 118.9, 108.1, 106.4, 100.9, 51.2, 25.3.
Methyl 1-(benzo[d][1,3]dioxol-6-yl)ethylcarbamate (54). To a solution of 8 (0.050 g, 0.16
mmol) in 0.5 mL methanol, sodium methoxide (0.086 g, 1.60 mmol) was added and the resulting
mixture was stirred at reflux for 1 h. The mixture was then cooled to room temperature and was
partitioned between dichloromethane and water (5 mL each). The organic layer was separated
and the aqueous was extracted with dichloromethane (2 x 5 mL). The combined organic layers
were dried over sodium sulfate and then filtered and concentrated to provide crude carbamate 54.
The crude residue was then purified by silica gel chromatography (5% ethyl acetate/ 95%
dichloromethane) to provide the pure carbamate 54 (0.025 g, 70%) as a colorless oil. TLC Rf =
0.23 (20% ethyl acetate/80% hexanes); IR (thin film) 3324, 2974, 2897, 1703, 1504 cmꢀ1; H
1
NMR (400 MHz, CDCl3) δ 6.79ꢀ6.74 (m, 3H), 5.94 (s, 2H), 4.91 (br s, 1H), 4.74 (br s, 1H), 3.65
13
(s, 3H), 1.44 (d, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 156.2, 147.8, 146.7, 137.7,
119.1, 108.3, 106.6, 101.0, 52.1, 50.5, 22.5; Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87; N,
6.27; Found: C, 59.10; H, 5.91; N, 6.35.
1-(1-(Benzo[d][1,3]dioxol-6-yl)ethyl)-3-benzylurea (55). To a solution of 8 (50.0 g, 0.16
mmol) in 0.6 mL DMF, Cs2CO3 (0.30 g, 0.96 mmol) and benzylamine (0.10 g, 0.96 mmol) were
added and the resulting mixture was stirred at room temperature for 18 h. The mixture was then
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diluted with saturated sodium bicarbonate solution and dichloromethane (5 mL each). The
organic layer was separated and the aqueous was extracted with dichloromethane (2 x 5 mL).
The combined organic layers were dried over sodium sulfate and then filtered and concentrated
to provide crude urea 55. The crude residue was then purified by silica gel chromatography (5%
ethyl acetate/ 95% dichloromethane) to provide the pure urea 55 (0.079 g, 82%) as a white solid.
mp = 143ꢀ147 °C; TLC Rf = 0.24 (40% ethyl acetate/60% toluene); IR (thin film) 3341, 3317,
3031, 2969, 2872, 1618, 1572 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.31ꢀ7.22 (m, 4H), 7.17 (d, J
= 6.8 Hz, 2H), 6.78ꢀ6.74 (m, 3H), 5.93 (s, 2H), 4.68 (q, J = 6.8 Hz, 1H), 4.36ꢀ4.27 (m, 2H), 5.04ꢀ
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3.96 (br s, 1H), 1.40 (d, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ 157.5, 148.1, 146.8,
138.9, 138.0, 128.6, 127.3, 119.0, 108.4, 106.4, 101.1, 77.2, 50.4, 44.5, 23.5; Anal. Calcd for
C17H18N2O3: C, 68.44; H, 6.08; N, 9.39; Found: C, 68.21; H, 5.88; N, 9.42.
Supporting Information Available
1
Copies of H NMR and 13C NMR spectra of new compounds and chiral HPLC data for
compound 4. This material is available free of charge via the Internet at http:// pubs.acs.org.
Author Information
Corresponding Author
*Eꢀmail: jdchisho@syr.edu
Notes
The authors declare no competing financial interest.
Acknowledgements
The National Institute of General Medical Sciences (R15ꢀGM116054) provided financial
support. Acknowledgement is also made to the Donors of the American Chemical Society
Petroleum Research Fund for a New Directions award in support of this research (54823ꢀND1).
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NMR spectra were obtained at Syracuse University using instrumentation acquired with the
assistance of the National Science Foundation (CHEꢀ1229345).
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